Substituted pyrimidin-4-one derivatives

ABSTRACT

A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof: 
                         
wherein Y, R1, R2, R3, and R4 are as defined in the disclosure. Also disclosed are methods of preparing the compounds of formula (I), intermediates thereof and their use in therapeutics.

This application is a continuation of International Application No.PCT/IB2009/006576, filed Jun. 25, 2009, which is incorporated herein byreference in its entirety; which claims the benefit of priority ofEuropean Patent Application No. 08290613.2 filed Jun. 26, 2008.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies.

Interestingly, protein kinase B (AKT) phosphorylation of GSK3β resultsin a loss of its kinase activity, and it has been hypothesized that thisinhibition may mediate some of the effects of neurotrophic factors.Moreover, phosphorylation by GSK3β of β-catenin, a protein involved incell survival, results in its degradation by an ubiquitinilationdependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as p53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseasesand other pathologies where GSK3β is deregulated (Nature reviews Vol. 3,June 2004, p. 479-487; Trends in Pharmacological Sciences Vol. 25 No. 9,September 2004, p. 471-480; Journal of neurochemistry 2004, 89,1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384, 2002).

The neurodegenerative diseases include, in a non-limiting manner,Parkinson's disease, tauopathies (e.g. Fronto temporal dementia,corticobasal degeneration, Pick's disease, progressive supranuclearpalsy), Wilson's disease, Huntington's disease (The Journal ofbiological chemistry Vol. 277, No. 37, Issue of September 13, pp.33791-33798, 2002), Prion disease (Biochem. J. 372, p. 129-136, 2003)and other dementia including vascular dementia; acute stroke and othertraumatic injuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis (European Journal of Neuroscience, Vol. 22, pp. 301-309, 2005)peripheral neuropathies; retinopathies and glaucoma. Recent studies havealso shown that inhibition of GSK3β results in neuronal differentiationof embryonic stem cells (ESC) and support the renewal of human and mouseESCs and the maintenance of their pluripotency. This suggests thatinhibitors of GSK3β could have applications in regenerative medicine(Nature Medicine 10, p. 55-63, 2004).

Inhibitors of GSK3β may also find application in the treatment of othernervous system disorders, such as bipolar disorders (manic-depressiveillness). For example lithium has been used for more than 50 years as amood stabiliser and the primary treatment for bipolar disorder. Thetherapeutic actions of lithium are observed at doses (1-2 mM) where itis a direct inhibitor of GSK3β. Although the mechanism of action oflithium is unclear, inhibitors of GSK3β could be used to mimic the moodstabilising effects of lithium. Alterations in Akt-GSK3β signaling havealso been implicated in the pathogenesis of schizophrenia.

In addition, inhibition of GSK3β could be useful in treating cancers,such as colorectal, prostate, breast, non-small cell lung carcinoma,thyroid cancer, T or B-cell leukaemia and several virus-induced tumours.For example, the active form of GSK3β has been shown to be elevated inthe tumors of colorectal cancer patients and inhibition of GSK3β incolorectal cancer cells activates p53-dependent apoptosis andantagonises tumor growth. Inhibition of GSK3β also enhancesTRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also playsa role in the dynamics of the mitotic spindle and inhibitors of GSK3βprevent chromosome movement and lead to a stabilization of microtubulesand a prometaphase-like arrest that is similar to that observed with lowdoses of Taxol. Other possible applications for GSK3β inhibitors includetherapy for non-insulin dependent diabetes (such as diabetes type II),obesity and alopecia.

Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog of thisenzyme found in Plasmodium falciparum, as a consequence they could beused for the treatment of malaria (Biochimica et Biophysica Acta 1697,181-196, 2004).

Recently, both human genetics and animal studies have pointed out therole of Wnt/LPR5 pathway as a major regulator of bone mass accrual.Inhibition of GSK3β leads to the consequent activation of canonical Wntsignalling. Because deficient Wnt signalling has been implicated indisorders of reduced bone mass, GSK3β inhibitors may also be used fortreating disorders of reduced bone mass, bone-related pathologies,osteoporosis.

According to recent data, GSK3β inhibitors might be used in thetreatment or prevention of Pemphigus vulgaris.

Recent studies show that GSK3beta inhibitor treatment improvesneutrophil and megakaryocyte recovery. Therefore, GSK3beta inhibitorswill be useful for the treatment of neutropenia induced by cancerchemotherapy.

Previous studies have shown that GSK3 activity decreases LTP, aelectrophysiological correlate of memory consolidation, suggesting thatinhibitor of this enzyme may have procognitive activity. Procognitiveeffects of the compound could find application for the treatment ofmemory deficits characteristic of Alzheimer's disease, Parkinsondisease, age-associated memory impairment, mild cognitive impairment,brain trauma, schizophrenia and other conditions in which such deficitsare observed.

Inhibitors of GSK3β may also find application in the treatment ofparenchymal renal diseases (Nelson P J, Kidney International Advanceonline publication 19 Dec. 2007) and in the prevention or treatment ofmuscle atrophy (J. Biol. Chem (283) 2008, 358-366)

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus provides as an object of the invention thepyrimidone derivatives represented by the formula (I) or salts thereof,solvates thereof or hydrates thereof:

wherein:

Y represents two hydrogen atoms, a sulphur atom, an oxygen atom;

R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring,the ring being optionally substituted by a C₁₋₆ alkyl group, a C₁₋₆alkoxy group or a halogen atom;

R2 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;

R3 represents

a phenyl- group, a phenyl-CH₂— group, a C₁₋₆ alkyl-O—C(O)— group, aphenyl-C(O)— group, a 5-10 membered heterocyclic group, aphenyl-CH₂—O—C(O)— group, a —C(O)-5-10 membered heterocyclic group,these groups being optionally substituted by 1 to 4 substituentsselected from a C₁₋₆ alkyl group, a halogen atom, a C₁₋₂ perhalogenatedalkyl group, a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₆alkoxy group, a C₁₋₂ perhalogenated alkoxy group, a C₁₋₆ alkylsulfonylgroup, a nitro, a cyano, an amino, a C₁₋₆ monoalkylamino group or aC₂₋₁₂ dialkylamino group, an acetoxy group, an aminosulfonyl group;

R4 represents a hydrogen atom, a halogen atom, a hydroxyl group, a C₁₋₆alkyl group;

m represents 0 to 2, in the form of a free base or of an addition saltwith an acid.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as:

Non-insulin dependent diabetes (such as diabetes type II) and obesity;malaria, bipolar disorders (manic depressive illness); schizophrenia;alopecia or cancers such as colorectal, prostate, breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukaemia,several virus-induced tumours and bone related pathologies; thetreatment of parenchymal renal diseases and in the prevention ortreatment of muscle atrophy; the treatment of cognitive and memorydeficit. The medicament could also find an application in regenerativemedicine.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the diseases are neurodegenerativediseases and are selected from the group consisting of Alzheimer'sdisease, Parkinson's disease, tauopathies (e.g. Fronto temporaldementia, corticobasal degeneration, Pick's disease, progressivesupranuclear palsy), Wilson's disease, Huntington's disease, Priondisease and other dementia including vascular dementia; acute stroke andothers traumatic injuries; cerebrovascular accidents (e.g. age relatedmacular degeneration); brain and spinal cord trauma; amyotrophic lateralsclerosis; peripheral neuropathies; retinopathies and glaucoma, and theaforementioned medicament in the form of pharmaceutical compositioncontaining the above substance as an active ingredient together with oneor more pharmaceutical additives.

As further embodiments of the present invention, there are provided theaforementioned medicament wherein the bones related pathologies areosteoporosis. The present invention further provides an inhibitor ofGSK3β activity comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives of formula (I)and the salts thereof, and the solvates thereof and the hydratesthereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof; and a use of a substance selected from the groupconsisting of the pyrimidone derivatives of formula (I) and thephysiologically acceptable salts thereof, and the solvates thereof andthe hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C_(x-t) group represents a group from x to t carbonatoms.

The alkyl group represents a straight or branched or cyclo alkyl groupoptionally substituted by a straight, branched or cyclic C₁₋₆ alkylgroup for example, methyl group, ethyl group, n-propyl group, isopropylgroup, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group,n-pentyl group, isopentyl group, neopentyl group, 1,1-dimethylpropylgroup, n-hexyl group, isohexyl group, cyclopropylmethyl, cyclopropylgroup, cyclopentyl group and the like.

The 5-10 membered heterocyclic group represents an unsaturated, fullysaturated or partially saturated mono- or polycyclic group (for example4 to 10 members) containing one to seven heteroatoms chosen from N, O,and S. Examples of heterocyclic groups include pyridine, pyrindine,pyrimidine, pyrazine, pyridazine, triazine, pyrrole, furan, thiophene,pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole,oxadiazole, thiazole, isothiazole, thiadiazole, pyrrolopyrrole,pyrroloimidazole, pyrrolopyrazole, pyrrolotriazole, imidazoimidazole,imidazopyrazole, imidazotriazole, quinoline, isoquinoline, cinnoline,phthalazine, quinoxaline, quinazoline, naphthyridine, benzotriazine,pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyridotriazine,pyrimidopyrimidine, pyrimidopyrazine, pyrimidopyridazine,pyrimidotriazine, pyrazinopyrazine, pyrazinopyridazine,pyrazinotriazine, pyridazinopyridazine, pyridazinotriazine, indole,isoindole, benzimidazole, indazole, indolizine, benzofuran,isobenzofuran, benzothiophene, benzo[c]thiophen, pyrrolopyridine,imidazopyridine, pyrazolopyridine, triazolopyridine, tetrazolopyridine,pyrrolopyrimidine, imidazopyrimidine, pyrazolopyrimidine,triazolopyrimidine, tetrazolopyrimidine, pyrrolopyrazine,imidazopyrazine, pyrazolopyrazine, triazolopyrazine, tetrazolopyrazine,pyrrolopyridazine, imidazopyridazine, pyrazolopyridazine,triazolopyridazine, tetrazolopyridazine, pyrrolotriazine,imidazotriazine, pyrazolotriazine, triazolotriazine, tetrazolotriazine,furopyridine, furopyrimidine, furopyrazine, furopyridazine,furotriazine, oxazolopyridine, oxazolopyrimidine, oxazolopyrazine,oxazolopyridazine, oxazolotriazine, isoxazolopyridine,isoxazolopyrimidine, isoxazolopyrazine, isoxazolopyridazine,isoxazolotriazine, oxadiazolopyridine, oxadiazolopyrimidine,oxadiazolopyrazine, oxadiazolopyridazine, oxadiazolotriazine,benzoxazole, benzisoxazole, benzoxadiazole, thienopyridine,thienopyrimidine, thienopyrazine, thienopyridazine, thienotriazine,thiazolopyridine, thiazolopyrimidine, thiazolopyrazine,thiazolopyridazine, thiazolotriazine, isothiazolopyridine,isothiazolopyrimidine, isothiazolopyrazine, isothiazolopyridazine,isothiazolotriazine, thiadiazolopyridine, thiadiazolopyrimidine,thiadiazolopyrazine, thiadiazolopyridazine, thiadiazolotriazine,benzothiazole, benzoisothiazole, benzothiadiazole, benzotriazole,benzodioxepine, benzodioxane, benzodioxine, diazepane. Theseheterocycles can exist also in a partially or fully saturated form, forexample as an illustration dihydrobenzofuran, tetrahydroquinoline etc. .. .

The C₁₋₆ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen atoms have been substituted by a halogen, for example aCF₃ or C₂F₅;

For

with Y represents two hydrogens atoms:

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast, one hydrogen has not been substituted by a halogen atom;

The C₁₋₆ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group, isopentylamino groupand the like;

The C₂₋₁₂ dialkylamino group represents an amino group substituted bytwo C₁₋₆ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group and the like;

a C₁₋₆ alkylsulfonyl group, represents a SO₂—C₁₋₆ alkyl group;

an acetoxy group represents a OC(O)Me;

an aminosulfonyl group represents a SO₂NH₂.

A leaving group L represents a group which could be easily cleaved andsubstituted; such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt. Examples of the salts include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid; salts with organic acidssuch as acetic acid, propionic acid, tartaric acid, fumaric acid, maleicacid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acidand the like.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the pyrimidone derivatives represented by theaforementioned formula (I) and salts thereof, their solvates andhydrates also fall within the scope of the present invention.

The pyrimidone derivatives represented by the aforementioned formula (I)may have one or more asymmetric carbon atoms. As for the stereochemistryof such asymmetric carbon atoms, they may independently be either (R) or(S) configuration, and the derivative may exist as stereoisomers such asoptical isomers, or diastereoisomers. Any stereoisomers in pure form,any mixtures of stereoisomers, racemates and the like fall within thescope of the present invention.

In a first embodiment of the invention, there is provided compoundswherein R1 represents an unsubstituted 4-pyridine ring or unsubstituted4-pyrimidine ring, in the form of a free base or of an addition saltwith an acid.

In a second embodiment of the invention, there is provided compoundswherein

wherein:

Y represents two hydrogen atoms, a sulphur atom, an oxygen atom;

R1 represents a 4-pyridine ring or a 4-pyrimidine ring,

R2 represents a hydrogen atom;

R3 represents

a phenyl- group, a phenyl-CH₂— group, a C₁₋₆ alkyl-O—C(O)— group, aphenyl-C(O)— group, a pyridine group, a phenyl-CH₂—O—C(O)— group, a—C(O)-pyridine group, a —C(O)benzodioxine group, these groups beingoptionally substituted by 1 to 4 substituents selected from a halogenatom, a C₁₋₆ alkoxy group;

R4 represents a hydrogen atom, a hydroxyl group, a C₁₋₆ alkyl group;

m represents 1 or 2, in the form of a free base or of an addition saltwith an acid.

Examples of compounds of the present invention are shown in table 1 andtable 2 hereinafter. However, the scope of the present invention is notlimited by these compounds. The nomenclature is given according to IUPACrules.

A further object of the present invention includes the group ofcompounds of table 1 of formula as defined hereunder:

-   1.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(2-methoxy-phenyl)-amide-   2.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(5-chloro-2-methoxy-phenyl)-amide-   3.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(4-chloro-2-methoxy-phenyl)-amide-   4.    (+/−)-9-Methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(4-chloro-2-methoxy-phenyl)-amide-   5.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(2-methoxy-benzyl)amide-   6.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(4-methoxy-benzyl)amide-   7.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(4-chloro-benzyl)amide-   8.    (+/−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide-   9.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid benzyl ester-   10.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid ethyl ester-   11.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid phenyl ester-   12.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid (4-fluoro-phenyl) ester-   13.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid (2-chloro-benzyl) ester-   14.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid (2-methoxy-ethyl) ester-   15.    (+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamic    acid (2-methoxy-phenyl(ester-   16.    (+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-nicotinamide-   17.    (+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide-   18.    (+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-nicotinamide-   19.    (+/−)-9-Hydroxy-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(2-methoxy-pyridin-3-yl)-amide-   20.    (+/−)-4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide-   21.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(pyridin-2-yl)amide-   22.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(2,6-dimethoxy-pyridin-3-yl)-amide-   23.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(pyridin-3-yl)amide-   24.    (+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic    acid N-(2-methoxy-pyridin-3-yl)-amide

A further object of the present invention includes the group ofcompounds of table 2 of formula as defined hereunder:

-   1.    (+/−)-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-carbamic    acid benzyl ester-   2.    (+/−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide-   3.    (+/−)-(10-Methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-carbamic    acid benzyl ester-   4. (+/−)-Pyridine-2-carboxylic acid    N-(10-methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-amide-   5. (+/−)-7-Fluoro-4H-benzo[1,3]dioxine-5-carboxylic acid    N-(10-methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-amide-   6.    (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylic    acid N-(2-methoxy-phenyl)-amide-   7.    (+/−)-2,6-Dimethoxy-N-(10-methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-nicotinamide-   8.    (−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide-   9.    (+)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide-   10.    (+/−)-2-Methoxy-N-(10-methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide-   11.    (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylic    acid N-(phenyl)amide-   12.    (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylic    acid N-(2,6-dimethoxy-pyridin-3-yl)-amide-   13.    (+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carbothioic    acid N-(5-chloro-2-methoxy-phenyl)-amide

As a further object, the present invention concerns also methods forpreparing the pyrimidone compounds represented by the aforementionedformula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Pyrimidone compounds represented by the aforementioned formula (I), maybe prepared according to the method described in the scheme 1.

(In the above scheme the definition of R1, R2, R3, R4 and m are the sameas those already described for compound of formula (I), Y represents asulphur atom or an oxygen atom, R represents an hydrogen or alkyl groupsuch as for example methyl or ethyl and L represents a leaving group).

Following this method, the pyrimidone derivative represented by theabove formula (II), wherein R1 and R2 are as defined for compound offormula (I), Y represents a sulphur atom or an oxygen atom and Rrepresents an alkyl group such as for example methyl or ethyl, isallowed to react in a solvent such as toluene, dimethylformamide, xyleneat a suitable temperature ranging from 80 to 130° C. under ordinary air,with a compound of formula (III), wherein R3 is as defined for compoundof formula (I) to obtain the compound of the aforementioned formula (I)wherein R4 represents a hydrogen atom.

Following this method, the pyrimidone derivative represented by theabove formula (I), wherein R1, R2, R3 and m are as defined for compoundof formula (I), Y represents a sulphur atom or an oxygen atom, R4represents a hydrogen atom, can also be deprotonated with strong basesuch as sodium hydride, bis(trimethylsilyl)amide or lithium diisopropylamide in a solvent such as ether, tetrahydrofuran, dimethylformamide andthe resultant anion can react with a suitable electrophile of formula(IV) wherein L represents a leaving group, such a group may be forexample a tosyl, a mesyl, a bromide and the like to afford the compoundof the aforementioned formula (I) wherein R4 is as defined for compoundof formula (I).

Compounds of formula (III) and (IV) are commercially available or may besynthesized according to well-known methods to one skilled in the art.

Compound of formula (II) may be prepared according to the method definedin scheme 2.

(In the above scheme, the definition of R1, R2 and m are the same asalready described for compound of formula (I), Y represents a sulphuratom or an oxygen atom, R and R′ represent an alkyl group such as forexample methyl or ethyl).

According to this method, the 3-ketoester of formula (V), wherein R1 andR2 are as defined for compound of formula (I), R′ is an alkyl group suchas for example methyl or ethyl is allowed to react with a compound offormula (VI), R is an alkyl group such as for example methyl or ethyl.The reaction may be carried out in the presence of a base such aspotassium carbonate or sodium methoxide in an alcoholic solvent such asmethanol, ethanol or an inert solvent such as toluene, xylene and thelike or without, at a suitable temperature ranging from 25° to 140° C.under ordinary air to obtain the compound of the aforementioned formula(II).

Additionally, compound of formula (II) wherein R2 represents a hydrogenatom may be halogenated in order to give compounds of formula (II)wherein R2 is a halogen atom such as a bromine atom or a chlorine atom.The reaction may be carried out in an acidic medium such as acetic acidor propionic acid, in presence of bromosuccinimide or chlorosuccimide,or bromine.

As a further object, the present invention concerns also the compoundsof formula (II) as intermediates of compounds of formula (I).

Compound of formula (V) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

For example compounds of formula (V), wherein R1 represents a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₆ alkyl group,a C₁₋₆ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₆ alkyl group, C₁₋₆ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

In addition, compounds of formula (V) wherein R2 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, No. 45, pp 6113-6116, 1989.

In addition, compounds of formula (V) wherein R2 represents a hydrogenatom may be obtained by analogy to the method described in patent DE2705582.

Compound of formula (VI) may be synthesized according to well-knownmethods of one skilled in the art. For example, it may be synthesized byanalogy to the methods described in Journal of Medicinal Chemistry,1994, 37 (17), 2774-2782.

Alternatively, compounds of formula (I) wherein R1, R2, R3, R4, Y, and mare as defined for compound of formula (I), may be prepared according tothe method defined in scheme 3, starting from compound of formula (VII).The conditions which may be used are given in the chemical examples.

(In the above scheme, the definition of R1, R2, R3, R4, Y and m are thesame as already described, L represents a leaving group and A representsa suitable electrophilic group which allows the preparation of thepyrimidone derivative represented by the above formula (I)).

According to this method, the pyrimidone derivative represented by theabove formula (VII), wherein R1, R2 and m are as defined for compound offormula (I), can be deprotonated with strong base such as sodiumhydride, lithium bis(trimethylsilyl)amide, lithium diisopropyl amide,n-butyl lithium, tert-butyl lithium or sec-butyl lithium in a solventsuch as ether, tetrahydrofuran, dimethylformamide and the resultantanion can react with a suitable electrophile. The resultant anion canreact with a compound of formula (IV) wherein R4 is defined for compoundof formula (I) and L represents a leaving group which could be easilycleaved and substituted; such a group may be for example a tosyl, amesyl, a bromide and the like. The resultant compound can bedeprotonated a second time with strong base such as sodium hydride,lithium bis(trimethylsilyl)amide, lithium diisopropyl amide, n-butyllithium, tert-butyl lithium or sec-butyl lithium in a solvent such asether, tetrahydrofuran, dimethylformamide and the resultant anion canreact with a suitable electrophile of formula (VIII) wherein R3 and Aare as defined for compound of formula (I) or as below to afford thecompound of the aforementioned formula (I).

Moreover, according to this method, the pyrimidone derivativerepresented by the above formula (VII), wherein R1, R2 and m are asdefined for compound of formula (I), can be deprotonated with strongbase such as sodium hydride, lithium bis(trimethylsilyl)amide, lithiumdiisopropyl amide, n-butyl lithium, tert-butyl lithium or sec-butyllithium in a solvent such as ether, tetrahydrofuran, dimethylformamideand the resultant anion can react directly with a compound of formula(VIII) wherein R3 and A are as defined above and below to afford thecompound of the aforementioned formula (I) wherein R4 represents ahydrogen atom.

Compounds of formula (IV) and (VIII) are commercially available or maybe synthesized according to well-known methods to one skilled in theart.

Compounds of formula (VIII) wherein A represents a suitableelectrophilic group. A is represented as follows:

Compound of formula (VII) may be prepared according to the methoddefined in scheme 4.

(In the above scheme, the definition of R1, R2 and m are the same asalready described and R represents an alkyl group such as for examplemethyl or ethyl).

According to this method, the 3-ketoester of formula (V), wherein R1 andR2 are as defined for compound of formula (I), R is an alkyl group suchas for example methyl or ethyl is allowed to react with a compound offormula (XI) wherein m is as defined for compound of formula (I). Thereaction may be carried out in the presence of a base such as potassiumcarbonate, sodium methoxide in an alcoholic solvent such as methanol,ethanol or an inert solvent such as toluene and the like or without, ata suitable temperature ranging from 25° to 140° C. under ordinary air toobtain the compound of the aforementioned formula (VII).

As a further object, the present invention concerns also the compoundsof formula (VII) as intermediates of compounds of formula (I).

Compound of formula (IX) with m represents 0, 1 or 2 may be synthesizedaccording to the methods described in WO96/14844 and in Journal ofMedicinal Chemistry (1998), 41(9), 1361-1366.

In the above reactions protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting groups, ofprotection and deprotection methods are given for example in Greene'sProtective Groups in Organic Synthesis, Greene et al., 4th Ed. (JohnWiley & Sons, Inc., New York) 2007.

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. Fronto temporal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy), Wilson's disease, Huntington'sdisease, Prion disease and other dementia including vascular dementia;acute stroke and others traumatic injuries; cerebrovascular accidents(e.g. age related macular degeneration); brain and spinal cord trauma;amyotrophic lateral sclerosis, peripheral neuropathies; retinopathiesand glaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; malaria, manic depressiveillness; schizophrenia; alopecia; cancers such as colorectal, prostatebreast cancer, non-small cell lung carcinoma, thyroid cancer, T orB-cell leukemia, several virus-induced tumours and in bone relatedpathologies; parenchymal renal diseases or muscle atrophy. Themedicament could also find an application in regenerative medicine. Themedicament could also find an application in the treatment or preventionof Pemphigus vulgaris. The medicament could also find an application inthe treatment of neutropenia induced by cancer chemotherapy. Themedicament could also find an application for therapeutic treatment of adisease characterized by cognitive and memory deficits such as inAlzheimer's disease, Parkinson disease, age associated memoryimpairment, mild cognitive impairment, brain trauma, schizophrenia andother conditions in which such deficits are observed.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention; however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound No. 3 of Table 1(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide 1.1(+/−)-4-oxo-2-pyrimidin-4-yl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid methyl ester

To a suspension of 23.50 g (121.99 mmol) of2-amino-3,4,5,6-tetrahydro-pyridine-3-carboxylic acid methyl esterhydrochloride (1:1) (synthesis as described in Journal of MedicinalChemistry (1994), 37(17), 2774-2782) in 240 mL of toluene was added27.91 mL (121.99 mmol) of sodium methoxide (25% wt. solution inmethanol). The reaction mixture was stirred at room temperature for 30min, 23.68 g (121.99 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionatewas added and the resulting mixture was stirred under reflux for 16hours. The mixture was dissolved in water and the resulting solid wasfiltrate rinsing with diethyl ether. The residue was purified by flashchromatography (dichloromethane with 2% to 10% of methanol) to afford12.00 g (34%) of a solid.

Mp: 174-176° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 9.42 (s, 0.6H), 9.30 (s, 0.4H), 9.02 (m, 1H), 8.30 (d, 0.6H),8.09 (d, 0.4H), 7.21 (s, 0.4H), 6.60 (m, 0.6H), 4.12 (m), 3.90 (m), 3.78(m), 3.74 (s, 1.2H), 3.88 (s, 1.8H), 2.38 (m), 2.11-1.90 (m), 1.78 (m),1.21 (m) (in a mixture with4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid (4-chloro-2-methoxy-phenyl)-amide in proportion of 60/40)

1.24-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide

To a suspension of 0.150 g (0.52 mmol) of(+/−)-4-oxo-2-pyrimidin-4-yl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid methyl ester in a sealed tube in 10.00 mL of toluene was added0.825 g (5.24 mmol) of 4-chloro-2-methoxy-phenylamine and the resultingmixture was stirred under reflux for 16 hours. The mixture was dissolvedin water and ethyl acetate. The organic phases were washed with asaturated aqueous solution of sodium chloride, dried over sodium sulfateand evaporated to dryness. The residue was purified by flashchromatography (dichloromethane/methanol/ammoniac in proportions of100/0/0 to 98/2/02) to afford 0.069 g (32%) of a solid.

Mp: 251-253° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 9.75 (m, 1H), 9.31, (m, 1H), 9.02 (d, 1H), 8.15 (d, 1H), 7.98(d, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.97 (d, 1H), 4.40 (m, 1H), 3.88(m, 2H), 3.75 (s, 3H), 2.22-1.98 (m, 4H).

Example 2 Compound No. 4 of Table 1(+/−)-9-Methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide

To a suspension of 0.100 g (0.24 mmol) of4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide (example 1) in 1.00 mL ofdimethylformamide was added 0.010 g (0.24 mmol) of sodium hydride at 0°C. and the resulting mixture was stirred at room temperature for 2hours. 0.020 mL (0.24 mmol) of methyl iodide was added and the mixturewas stirred at room temperature for 1 hour. The mixture was dissolved inwater and dichloromethane. The organic phases were washed with asaturated aqueous solution of sodium chloride, dried over sodium sulfateand evaporated to dryness. The residue was purified by flashchromatography (cyclohexane/ethyl acetate in proportions of 80/20 to70/30) to afford 0.053 g (51%) of a solid.

Mp: 210-212° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.61 (br s, 1H), 9.40 (s, 1H), 9.00 (d, 1H), 8.38 (d, 1H), 8.31(d, 1H), 7.60 (s, 1H), 6.92 (dd, 1H), 6.72 (d, 1H), 4.22 (m, 2H), 3.76(m, 1H), 3.30 (s, 3H), 2.98 (m, 1H), 1.90 (s, 3H), 2.12 (m, 2H).

Example 3 Compound No. 5 of Table 14-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-benzyl)amide

By analogy with the method described in example 1 (step 1.2), using2-methoxy-benzylamine in place of 4-chloro-2-methoxy-phenylamine, 0.085g of the compound (62%) was obtained as a white powder.

Mp: 181-183° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.32 (s, 1H), 8.79 (m, 1H), 7.82 (d, 1H), 7.53 (m, 1H), 7.31(m, 3H), 6.87 (m, 2H), 4.45 (m, 2H), 4.10-3.85 (m, 3H), 3.65 (s, 3H),2.61 (m, 1H), 2.08 (m, 3H).

Example 4 Compound No. 9 of Table 1(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid benzyl ester 4.12-Pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one

To a suspension of 25.0 g (185.72 mmol) of3,4,5,6-tetrahydro-pyridin-2-ylamine monohydrochloride in 138 mL ofethanol was added 25.67 g (185.72 mmol) of potassium carbonate. Thereaction mixture was stirred at room temperature for 10 min, 36.06 g(185.72 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added andthe resulting mixture was stirred under reflux for 16 h. The cooledsolution was evaporated to remove solvent. The mixture was dissolved inethylacetate, washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate and evaporated to dryness. Theresulting solid was triturated in diethyl ether, filtrated to afford9.23 g (22%) of the desired compound as a white-brown powder.

Mp: 177-179° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.32 (s, 1H), 9.05 (d, 1H), 8.25 (d, 1H), 7.22 (s, 1H), 3.89(m, 2H), 3.00 (m, 2H), 1.98-1.88 (m, 4H).

4.2(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid benzyl ester

To a solution of 0.300 g (1.31 mmol) of2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one in drytetrahydrofuran (7.00 mL) under argon at −78° C. was added 2.76 mL (2.76mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). Thesolution was stirred at −78° C. for 30 min and 0.408 g (1.45 mmol) ofcarbamic acid, (1H-benzotriazol-1-ylmethyl)-, phenylmethyl ester(synthesis as described in Journal of Organic Chemistry (2002), 67(14),4957-4959) in 2.00 mL of dry tetrahydrofuran was added. The reaction wasstirred at −78° C. for 3 hours. The mixture was quenched with theaddition of water and extracted with ethyl acetate. The organic phasewas dried over sodium sulfate and concentrated. The residue was purifiedby flash chromatography cyclohexane with 10 à 50% of ethyl acetate) toafford 0.132 g of a white solid (25%).

Mp: 138-140° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.32 (s, 1H), 9.02 (d, 1H), 8.30 (d, 1H), 7.45 (br s, 1H), 7.38(m, 5H), 7.22 (s, 1H), 5.07 (m, 2H), 3.90 (m, 2H), 3.80 (m, 1H), 3.51(m, 1H), 3.15 (m, 1H), 2.05-1.89 (m, 2H), 1.70 (m, 1H), 1.54 (m, 1H).

Example 5 Compound No. 8 of Table 1 (+/−)4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide

To a solution of 0.080 g (0.20 mmol) of(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid benzyl ester (example 4) dissolved in 2.00 mL of glacial aceticacid was added 0.180 mL (1.02 mmol) of hydrobromic acid (33 wt %solution in glacial acetic acid). The resulting mixture was stirred atroom temperature for 2.5 hours and evaporated to dryness. Toluene wasadded to the residue and evaporated. Ethanol was added to the residueand evaporated. The compound was used as such in the next step.

To a solution of 0.067 g (0.20 mmol) of9-aminomethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-onehydrobromide (1:1) dissolved in 2.00 mL of dimethylformamide were added0.053 g (0.20 mmol) of 4-chloro-2-methoxy-benzoic acid, 0.030 mL (0.20mmol) of diethylcyanophosphonate and 0.140 mL (1.00 mmol) oftriethylamine. The resulting mixture was stirred at room temperature for2 hours. Water and ethyl acetate were added, the mixture was extractedwith ethyl acetate and the organic phase was washed with a saturatedsolution of ammonium chloride, dried over sodium sulfate andconcentrated. A purification on silica gel (eluant: dichloromethane with5% of methanol) gave 0.049 g (57%) of pure product obtained in the formof free base as a solid.

Mp: 188-190° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.33 (s, 1H), 9.01 (d, 1H), 8.38 (m, 1H), 8.28 (d, 1H), 7.72(d, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.09 (m, 1H), 4.02 (m, 2H), 3.82(m, 2H), 3.72 (s, 3H), 2.08 (m, 1H), 1.98 (m, 2H), 1.72 (m, 1H).

Example 6 Compound No. 3 of Table 2(+/−)-(10-Methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-carbamicacid benzyl ester 6.12-Pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one

To a suspension of 77.9 g (524.1 mmol) of 2H-azepin-7-amine,3,4,5,6-tetrahydro, monohydrochloride (synthesis as described inWO96/14844 or in Journal of Medicinal Chemistry (1998), 41(9),1361-1366) in 390 mL of ethanol was added 72.4 g (524.1 mmol) ofpotassium carbonate. The reaction mixture was stirred at roomtemperature for 10 min, 101.7 g (524.1 mmol) of ethyl3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixturewas stirred under reflux for 16 h. The cooled solution was evaporated toremove solvent. The mixture was dissolved in dichloromethane, washedwith a saturated aqueous solution of sodium chloride, dried over sodiumsulfate and evaporated to dryness. The residue was filtrate through apad of silica, rinsing with dichloromethane and then ethyl acetate.After evaporation, the resulting solid was triturated in diethyl ether,filtrated to afford 36.4 g (28%) of the desired compound as awhite-brown powder.

Mp: 148-150° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.32 (s, 1H), 9.01 (d, 1H), 8.24 (d, 1H), 7.21 (s, 1H), 4.32(m, 2H), 3.11 (m, 2H), 1.66-1.83 (m, 6H).

6.2(+/−)-10-Methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one

To a solution of 10.00 g (41.27 mmol) of2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one indry tetrahydrofuran (200 mL) under argon at −78° C. was added 82.5 mL(82.5 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran).The solution was stirred at −78° C. for 10 min and 25.7 mL of methyliodide (412.7 mmol) was added. The reaction was stirred at −78° C. for 1h and then at 0° C. for 2 h. The mixture was quenched with the additionof a saturated solution of ammonium chloride and extracted with ethylacetate. The organic phase was dried over sodium sulfate andconcentrated. The residue was purified by flash chromatography(dichloromethane with 1% of methanol) to afford 11.0 g of a white solid(40%).

Mp: 182-184° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.31 (s, 1H), 9.03 (d, 1H), 8.30 (d, 1H), 7.22 (s, 1H), 5.02(m, 1H), 3.70 (m, 1H), 3.40 (m, 1H), 2.00 (m, 1H), 1.78-1.90 (m, 3H),1.30-1.48 (m, 5H).

6.3(+/−)-(10-Methyl-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-carbamicacid benzyl ester

By analogy with the method described in example 4 (step 4.2), using(+/−)-10-methyl-2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-onein place of2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one, 0.050g of the compound (30%) was obtained as a white powder.

Mp: 118-120° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.33 (s, 1H), 9.08 (d, 1H), 8.25 (d, 1H), 7.38 (br s, 1H), 7.22(m, 6H), 4.95 (m, 2H), 4.42 (m, 2H), 3.75 (m, 1H), 3.50 (m, 1H), 1.96(m, 1H), 1.75 (m, 5H), 1.49 (s, 3H).

Example 7 Compound No. 8 of Table 2(−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide

0.139 g (0.316 mmol) of(+/−)-4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamidewas separated by chiral preparative HPLC(CHIRALPAK T304 20 μm) elutingwith acetonitrile/isopropanol (95/5) to give 0.071 g of pure productobtained in the form of free base.

Mp: 130-140° C. [α]_(D) ²⁰=−90.5° (c=5.046, MeOH).

RMN ¹H (DMSO; 400 MHz)

δ (ppm): 9.40 (s, 1H), 9.08 (s, 1H), 8.50-8.30 (m, 2H), 7.85 (d, 1H),7.30 (s, 1H), 7.25-7.10 (m, 2H), 5.00 (d, 1H), 4.00-3.60 (m, 4H), 3.55(s, 3H), 2.10-1.20 (m, 6H).

Example 8 Compound No. 9 of Table 2(+)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamide

0.139 g (0.316 mmol) of(+/−)-4-chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-benzamidewas separated by chiral preparative HPLC (CHIRALPAK T304 20 μm) elutingwith acetonitrile/isopropanol (95/5) to give 0.063 g of pure productobtained in the form of free base.

Mp: 130-140° C. [α]_(D) ²⁰=+93.3° (c=4.298, MeOH).

RMN ¹H (DMSO; 400 MHz)

δ (ppm): 9.40 (s, 1H), 9.08 (s, 1H), 8.50-8.30 (m, 2H), 7.85 (d, 1H),7.30 (s, 1H), 7.25-7.10 (m, 2H), 5.00 (d, 1H), 4.00-3.60 (m, 4H), 3.55(s, 3H), 2.10-1.20 (m, 6H).

Example 9 Compound No. 12 of Table 2(+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylicacid N-(2,6-dimethoxy-pyridin-3-yl)-amide 9.1(+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylicacid (4-nitro-phenyl) ester

To a solution of 0.500 g (2.06 mmol) of2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one(step 6.1 of example 6) in dry tetrahydrofuran (20 mL) under argon at−40° C. was added 2.27 mL (2.27 mmol) of lithiumbis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution wasstirred at −50° C. for 10 min and 1.04 g (5.16 mmol) of 4-nitrophenylchloroformate diluted in 3 ml of dry tetrahydrofuran was added. Themixture was quenched with the addition of a saturated solution ofammonium chloride and extracted with dichloromethane. The organic phasewas dried over sodium sulfate and concentrated. The residue was used assuch for the next step.

9.2(+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylicacid N-(2,6-dimethoxy-pyridin-3-yl)-amide

To a solution of 0.450 g (1.10 mmol) of(+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carboxylicacid 4-nitro-phenyl ester in 10 mL of dry acetonitrile in a sealed tube,were added 0.341 g (2.21 mmol) of 2,6-dimethoxy-pyridin-3-ylamine and0.270 g (2.21 mmol) of dimethyl-pyridin-4-yl-amine. The resultingmixture was stirred under reflux for 16 hours. The mixture was dissolvedin water and dichloromethane. The organic phases were washed with asaturated aqueous solution of sodium chloride, dried over sodium sulfateand evaporated to dryness. The residue was purified by flashchromatography (dichloromethane/methanol/ammoniac in proportions of100/0/0 to 98/2/02) to afford 0.121 g (26%) of a white solid.

Mp: 231-233° C.

RMN ¹H (DMSO; 400 MHz)

δ (ppm): 9.35 (s, 1H), 9.30 (s, 1H), 9.00 (d, 1H), 8.30 (d, 1H), 8.00(d, 1H), 7.25 (s, 1H), 6.45 (d, 1H), 5.00 (m, 1H), 4.45 (m, 1H), 3.90(s, 6H), 3.80 (m, 1H), 2.25 (m, 1H), 2.05-1.70 (m, 4H), 1.40 (m, 1H).

Example 10 Compound No. 13 of Table 2(+/−)-4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine-10-carbothioicacid N-(5-chloro-2-methoxy-phenyl)-amide

To a solution of 0.400 g (1.65 mmol) of2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one(step 1 of example 6) in 16 mL of dry tetrahydrofuran at −50° C., wasadded 1.82 mL (1.82 mmol) of lithium bis(trimethylsilyl)amide (1M intetrahydrofuran). The resulting mixture was stirred at −50° C. for 10min. 0.494 g (2.48 mmol) of 4-chloro-2-isothiocyanato-1-methoxy-benzenedissolved in 2 mL of tetrahydrofuran was added at −50° C. the resultingmixture was stirred for 2 hours. The mixture was dissolved in asaturated solution of ammonium chloride and dichloromethane. The organicphases were washed with a saturated aqueous solution of sodium chloride,dried over sodium sulfate and evaporated to dryness. The residue waspurified by flash chromatography (dichloromethane/methanol/ammoniac inproportions of 99/1/0.1 to 98/2/0.2) to afford 0.224 g (31%) of a solid.

Mp: 220-223° C.

RMN ¹H (DMSO; 400 MHz)

δ (ppm): 11.10 (br s, 1H), 9.33 (s, 1H), 9.02 (d, 1H), 8.20 (d, 1H),7.92 (m, 1H), 7.38 (m, 1H), 7.28 (s, 1H), 7.14 (m, 1H), 4.90 (m, 1H),4.70 (m, 1H), 3.91 (m, 1H), 3.72 (s, 3H), 2.05-1.82 (m, 5H), 1.48 (m,1H).

Example 11 Compound No. 19 of Table 1(+/−)-9-Hydroxy-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-pyridin-3-yl)-amide

To a solution of 0.200 g (0.70 mmol) of(+/−)-4-oxo-2-pyrimidin-4-yl-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid methyl ester (example 1, step 1.1) in 3.5 mL of toluene in a sealedtube, was added 0.867 g (6.99 mmol) of 2-methoxy-pyridin-3-ylamine. Theresulting mixture was stirred at 140° C. for 24 hours. The mixture wasdissolved in a saturated solution of ammonium chloride anddichloromethane. The organic phases were washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate and evaporated todryness. The residue was purified by flash chromatography(dichloromethane/methanol/ammoniac in proportions of 95/5/0.5) to afford0.032 g (12%) of a grey solid.

Mp: 208-210° C.

RMN ¹H (DMSO; 400 MHz)

δ (ppm): 9.23 (s, 1H), 8.90 (d, 1H), 8.36 (d, 1H), 8.09 (d, 1H), 7.30(d, 1H), 7.91 (m, 1H), 7.01 (s, 1H), 3.95 (s, 3H), 4.11 (m, 1H), 3.75(m, 1H), 2.38 (m, 1H), 2.12 (m, 3H)

Example 12 Compound No. 1 of Table 2(+/−)-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepin-10-ylmethyl)-carbamicacid benzyl ester

By analogy with the method described in example 4 (step 4.2), using2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one inplace (example 6, step 6.1) of2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one, 0.500g of the compound (31%) was obtained as a white powder.

Mp: 179-181° C.

RMN ¹H (DMSO-d⁶; 400 MHz)

δ (ppm): 9.40 (s, 1H), 9.00 (d, 1H), 8.30 (m, 1H), 7.35 (m, 6H), 7.25(s, 1H), 5.05 (m, 3H), 3.85 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H),1.95-1.70 (m, 4H), 1.45 (m, 2H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 1. The compounds have been prepared according to the methods ofthe examples.

In the table 1, m represents 1, Me represents a methyl group, (Rot.)indicates the levorotatory or dextrorotatory properties of theenantiomeric compound, (dec.) indicates the decomposition of thecompound. Table 1A provides analytical data for the compounds of Table1.

TABLE 1 (I)

No. Rot R3 R1 R4 R2 Y salt 1 (+/−)

H H O Free base 2 (+/−)

H H O Free base 3 (+/−)

H H O Free base 4 (+/−)

Me H O Free base 5 (+/−)

H H O Free base 6 (+/−)

H H O Free base 7 (+/−)

H H O Free base 8 (+/−)

H H H, H Free base 9 (+/−)

H H H, H Free base 10 (+/−)

H H H, H Free base 11 (+/−)

H H H, H Free base 12 (+/−)

H H H, H Free base 13 (+/−)

H H H, H Free base 14 (+/−)

H H H, H Free base 15 (+/−)

H H H, H Free base 16 (+/−)

H H H, H Free base 17 (+/−)

H H H, H Free base 18 (+/−)

H H H, H Free base 19 (+/−)

OH H O Free base 20 (+/−)

H H H, H Free base 21 (+/−)

H H O Free base 22 (+/−)

H H O Free base 23 (+/−)

H H O Free base 24 (+/−)

H H O Free base

TABLE 1A N^(o) Mp° C. NMR 1 147-149 200 MHz DMSO δ (ppm): 9.70 (br s,1H); 9.40 (s, 1H); 9.0 (d, 1H); d6 8.20 (d, 1H); 7.90 (d, 1H); 7.20 (s,1H); 7.10-6.70 (m, 3H); 4.40 (t, 1H); 3.90 (m, 2H); 3.70 (s, 3H);2.20-1.80 (m, 4H). 2 162-164 200 MHz DMSO δ (ppm): 9.80 (br s, 1H); 9.30(s, 1H); 9.0 (d, 1H); d6 8.10 (m, 2H); 7.20 (d, 1H); 7.20 (s, 1H); 7.10(m, 2H); 4.40 (t, 1H); 3.80 (m, 2H); 3.70 (s, 3H); 2.20-1.80 (m, 4H). 3251-253 200 MHz DMSO δ (ppm): 9.75 (m, 1H), 9.31, (m, 1H), 9.02 (d, 1H),8.15 (d, 1H), d6 7.98 (d, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.97 (d, 1H),4.40 (m, 1H), 3.88 (m, 2H), 3.75 (s, 3H), 2.22-1.98 (m, 4H). 4 210-212200 MHz CDCl3 δ (ppm): 9.61 (br s, 1H), 9.40 (s, 1H), 9.00 (d, 1H), 8.38(d, 1H), 8.31 (d, 1H), 7.60 (s, 1H), 6.92 (dd, 1H), 6.72 (d, 1H), 4.22(m, 2H), 3.76 (m, 1H), 3.30 (s, 3H), 2.98 (m, 1H), 1.90 (s, 3H), 2.12(m, 2H). 5 181-183 200 MHz CDCl3 δ (ppm): 9.32 (s, 1H), 8.79 (m, 1H),7.82 (d, 1H), 7.53 (m, 1H), 7.31 (m, 3H), 6.87 (m, 2H), 4.45 (m, 2H),4.10-3.85 (m, 3H), 3.65 (s, 3H), 2.61 (m, 1H), 2.08 (m, 3H). 6 192-193200 MHz CDCl3 δ (ppm): 9.30 (s, 1H); 8.70 (s, 1H); 7.70 (d, 1H); 7.50(br s, 1H); 7.40 (br s, 1H); 7.30 (s, 1H); 7.20 (d, 2H); 6.80 (d, 2H);4.40 (d, 2H); 4.20-3.90 (m, 3H); 3.80 (s, 3H); 2.70 (m, 1H); 2.20-1.90(m, 3H). 7 189-191 200 MHz CDCl3 δ (ppm): 9.40 (s, 1H); 8.80 (d, 1H);7.70 (d, 1H); 7.60-7.40 (m, 2H); 7.30-7.10 (m, 4H); 4.50 (d, 2H);4.20-3.70 (m, 3H); 2.70 (m, 1H); 2.20-1.90 (m, 3H). 8 188-190 400 MHzDMSO δ (ppm): 9.33 (s, 1H), 9.01 (d, 1H), 8.38 (m, 1H), d6 8.28 (d, 1H),7.72 (d, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.09 (m, 1H), 4.02 (m, 2H),3.82 (m, 2H), 3.72 (s, 3H), 2.08 (m, 1H), 1.98 (m, 2H), 1.72 (m, 1H). 9138-140 400 MHz DMSO δ (ppm): 9.32 (s, 1H), 9.02 (d, 1H), 8.30 (d, 1H),d6 7.45 (br s, 1H), 7.38 (m, 5H), 7.22 (s, 1H), 5.07 (m, 2H), 3.90 (m,2H), 3.80 (m, 1H), 3.51 (m, 1H), 3.15 (m, 1H), 2.05-1.89 (m, 2H), 1.70(m, 1H), 1.54 (m, 1H). 10 166-168 400 MHz DMSO δ (ppm): 9.30 (s, 1H);9.00 (d, 1H); 8.30 (d, 1H); d6 7.25 (s, 2H); 4.10-3.80 (m, 4H); 3.70 (m,1H); 3.45 (m, 1H); 3.15 (m, 1H); 2.20-1.80 (m, 3H); 1.65 (m, 1H); 1.15(t, 3H). 11 190-192 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H);8.30 (d, 1H); 7.90 (t, 1H); d6 7.40 (m, 2H); 7.20 (m, 2H); 7.10 (m, 2H);4.00-3.80 (m, 3H); 3.60 (m, 1H); 3.20 (m, 1H); 2.20-1.90 (m, 3H); 1.70(m, 1H). 12 199-201 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H);8.30 (d, 1H); d6 7.90 (t, 1H); 7.30-7.10 (m, 4H); 3.90 (m, 3H); 3.60 (m,1H); 3.20 (m, 1H); 2.20-1.90 (m, 3H); 1.70 (m, 1H). 13 135-140 400 MHzDMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.30 (d, 1H); 7.50 (m, 3H); d67.35 (m, 2H); 7.20 (s, 1H); 5.10 (m, 2H); 3.95-3.75 (m, 3H); 3.50 (m,1H); 3.20 (m, 1H); 2.20-1.85 (m, 3H); 1.70 (m, 1H). 14 110-112 400 MHzDMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.30 (d, 1H); 7.40 (t, 1H); d67.20 (s, 1H); 4.20 (m, 2H); 3.90 (t, 2H); 3.80 (m, 1H); 3.50 (m, 3H);3.30 (s, 3H); 3.15 (m, 1H); 2.20-1.80 (m, 3H); 1.70 (m, 1H). 15 188-190400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.30 (d, 1H); d6 7.85(t, 1H); 7.30-6.90 (m, 4H); 3.90 (m, 2H); 3.85 (m, 1H); 3.75 (s, 3H);3.20 (m, 1H); 2.10-1.80 (m, 3H); 1.70 (m, 1H). 16 185-187 300 MHz DMSO δ(ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.30 (m, 2H); 8.20 (d, 1H); d6 7.25(s, 1H); 6.50 (d, 1H); 4.20-3.95 (m, 2H); 3.90 (s, 3H); 3.80 (m, 1H);3.30 (m, 2H); 2.20-1.85 (m, 3H); 1.70 (m, 1H). 17 136-138 400 MHz DMSO δ(ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.40 (t, 1H); d6 8.30 (d, 1H); 7.80(d, 1H); 7.50 (m, 1H); 7.30 (s, 1H); 7.15 (d, 1H); 7.05 (t, 1H); 4.10-(m, 2H); 3.85 (m, 2H); 3.70 (s, 3H); 2.20-1.85 (m, 3H); 1.70 (m, 1H). 18153-155 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.40 (t, 1H);8.25 (m, 2H); d6 8.15 (m, 1H); 7.30 (s, 1H); 7.15 (m, 1H); 4.05 (m, 2H);3.85 (m, 2H); 3.75 (s, 3H); 2.20-1.85 (m, 3H); 1.70 (m, 1H). 19 208-210400 MHz DMSO δ (ppm): 9.23 (s, 1H), 8.90 (d, 1H), 8.36 (d, 1H), 8.09 (d,1H), d6 7.30 (d, 1H), 7.91 (m, 1H), 7.01 (s, 1H), 3.95 (s, 3H), 4.11 (m,1H), 3.75 (m, 1H), 2.38 (m, 1H), 2.12 (m, 3H) 20 162-164 400 MHz DMSO δ(ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.40 (t, 1H); d6 8.30 (d, 1H); 7.80(m, 1H); 7.25 (s, 1H); 7.05 (d, 1H); 6.90 (m, 1H); 4.05 (m, 2H); 3.85(m, 2H); 3.75 (s, 3H); 3.30 (m, 1H); 2.20-1.85 (m, 3H); 1.70 (m, 1H). 21184-185 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.40 (s, 1H);d6 8.10 (m, 2H); 7.80 (m, 1H); 7.30 (s, 1H); 7.20 (m, 1H); 4.40 (t, 1H);3.90 (m, 2H); 2.35-2.10 (m, 3H); 2.00 (m, 1H). 22 160-161 400 MHz DMSO δ(ppm): 9.70 (s, 1H); 9.35 (s, 1H); 9.00 (d, 1H); 8.25 (d, 1H); d6 8.10(d, 1H); 7.25 (s, 1H); 6.40 (d, 1H); 4.35 (t, 1H); 4.00-3.90 (m, 5H);3.85 (s, 3H); 2.30-2.10 (m, 3H); 2.00 (m, 1H). 23 191-193 400 MHz DMSO δ(ppm): 9.35 (s, 1H); 9.00 (d, 1H); 8.80 (s, 1H); d6 8.35 (s, 1H); 8.10(m, 2H); 7.40 (m, 1H); 7.25 (s, 1H); 4.25 (t, 1H); 3.95 (m, 2H);2.30-2.10 (m, 3H); 2.00 (m, 1H). 24 194-196 400 MHz DMSO δ (ppm): 9.90(s, 1H); 9.35 (s, 1H); 9.05 (d, 1H); 8.35 (d, 1H); d6 8.25 (m, 1H); 8.00(m, 1H); 7.30 (s, 1H); 7.00 (m, 1H); 4.45 (t, 1H); 4.00-3.80 (m, 5H);2.30-2.10 (m, 3H); 2.00 (m, 1H).

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin table 2. The compounds have been prepared according to the methods ofthe examples.

In the table 2, m represents 2, Me represents a methyl group, (Rot.)indicates the levorotatory or dextrorotatory properties of theenantiomeric compound, (dec.) indicates the decomposition of thecompound. Table 2A provides analytical data for the compounds of Table2.

TABLE 2 (I)

No. Rot R3 R1 R4 R2 Y salt 1 (+/−)

H H H, H Free base 2 (+/−)

H H H, H Free base 3 (+/−)

Me H H, H Free base 4 (+/−)

Me H H, H Free base 5 (+/−)

Me H H, H Free base 6 (+/−)

H H O Free base 7 (+/−)

Me H H, H Free base 8 (−)

H H H, H Free base 9 (+)

H H H, H Free base 10 (+/−)

Me H H, H Free base 11 (+/−) Ph

H H O Free base 12 (+/−)

H H O Free base 13 (+/−)

H H S Free base

TABLE 2A N^(o) Mp° C. NMR 1 179-181 400 MHz DMSO δ (ppm): 9.40 (s, 1H),9.00 (d, 1H), 8.30 (m, 1H), d6 7.35 (m, 6H), 7.25 (s, 1H), 5.05 (m, 3H),3.85 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H), 1.95-1.70 (m, 4H), 1.45 (m,2H). 2 173-175 400 MHz DMSO δ (ppm): 9.40 (s, 1H); 9.10 (d, 1H); 8.40(m, 2H); d6 7.85 (m, 1H); 7.30 (s, 1H); 7.20-7.00 (m, 2H); 5.00 (m, 1H);4.00-3.80 (m, 2H); 3.70 (t, 1H); 3.50 (s, 3H); 2.10-1.70 (m, 4H);1.50-1.20 (m, 2H). 3 118-120 400 MHz DMSO δ (ppm): 9.33 (s, 1H), 9.08(d, 1H), 8.25 (d, 1H), 7.38 (br s, 1H), d6 7.22 (m, 6H), 4.95 (m, 2H),4.42 (m, 2H), 3.75 (m, 1H), 3.50 (m, 1H), 1.96 (m, 1H), 1.75 (m, 5H),1.49 (s, 3H). 4 175-177 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.00 (d,2H); 8.50 (d, 1H); d6 8.30 (d, 1H); 8.00 (m, 2H); 7.60 (m, 1H); 7.30 (s,1H); 4.80 (br s, 1H); 4.20 (br s, 1H); 4.00 (m, 1H); 3.80 (m, 1H); 2.00(m, 1H); 1.80-1.60 (m, 5H); 1.45 (s, 3H). 5 147-149 400 MHz DMSO δ(ppm): 9.35 (s, 1H); 9.05 (d, 1H); 8.45 (t, 1H); d6 8.30 (d, 1H); 7.35(m, 1H); 7.30 (s, 1H); 7.10 (m, 1H); 4.90 (d, 4H); 4.75 (m, 1H); 4.15(m, 1H); 4.10 (m, 1H); 3.80 (m, 1H); 2.00 (m, 1H); 1.80-1.60 (m, 5H);1.50 (s, 3H). 6 221-223 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.30 (s,1H); 9.00 (d, 1H); d6 8.25 (d, 1H); 8.00 (s, 1H); 7.30 (s, 1H);7.15-6.95 (m, 3H); 5.00 (m, 1H); 4.45 (m, 1H); 3.90 (s, 3H); 3.80 (s,4H); 2.25 (m, 1H); 2.05-1.70 (m, 4H); 1.40 (m, 1H). 7 189-191 400 MHzDMSO δ (ppm): 9.35 (s, 1H); 9.05 (d, 1H); 8.40 (t, 1H); 8.30 (d, 1H); d68.20 (d, 1H); 7.30 (s, 1H); 6.50 (d, 1H); 4.85 (m, 1H); 4.00 (m, 2H);3.90 (s, 3H); 3.85 (m, 1H); 3.50 (s, 3H); 2.00 (m, 1H); 1.80 (m, 3H);1.60 (m, 2H); 1.50 (s, 3H). 8 130-140 400 MHz DMSO δ (ppm): 9.40 (s,1H), 9.08 (s, 1H), 8.50-8.30 (m, 2H), d6 7.85 (d, 1H), 7.30 (s, 1H),7.25-7.10 (m, 2H), 5.00 (d, 1H), 4.00-3.60 (m, 4H), 3.55 (s, 3H),2.10-1.20 (m, 6H). 9 130-140 400 MHz DMSO δ (ppm): 9.40 (s, 1H), 9.08(s, 1H), 8.50-8.30 (m, 2H), d6 7.85 (d, 1H), 7.30 (s, 1H), 7.25-7.10 (m,2H), 5.00 (d, 1H), 4.00-3.60 (m, 4H), 3.55 (s, 3H), 2.10-1.20 (m, 6H).10 130-132 400 MHz DMSO δ (ppm): 9.35 (s, 1H); 9.05 (d, 1H); 8.50 (t,1H); 8.30 (d, 1H); d6 7.80 (d, 1H); 7.45 (m, 1H); 7.30 (s, 1H); 7.00 (m,2H); 4.75 (m, 1H); 4.20-4.00 (m, 2H); 3.80 (m, 1H); 3.50 (s, 3H); 2.00(m, 1H); 1.80 (m, 3H); 1.60 (m, 2H); 1.50 (s, 3H). 11 228-230 400 MHzDMSO δ (ppm): 9.90 (s, 1H); 9.30 (s, 1H); 8.90 (d, 1H); d6 7.90 (d, 1H);7.60 (m, 2H); 7.40 (m, 2H); 7.30 (s, 1H); 7.10 (m, 1H); 5.00 (m, 1H);4.45 (m, 1H); 3.80 (t, 1H); 2.30 (m, 1H); 2.05-1.70 (m, 4H); 1.40 (m,1H). 12 231-233 400 MHz DMSO δ (ppm): 9.35 (s, 1H), 9.30 (s, 1H), 9.00(d, 1H), d6 8.30 (d, 1H), 8.00 (d, 1H), 7.25 (s, 1H), 6.45 (d, 1H), 5.00(m, 1H), 4.45 (m, 1H), 3.90 (s, 6H), 3.80 (m, 1H), 2.25 (m, 1H),2.05-1.70 (m, 4H), 1.40 (m, 1H). 13 220-223 400 MHz DMSO δ (ppm): 11.10(br s, 1H), 9.33 (s, 1H), 9.02 (d, 1H), d6 8.20 (d, 1H), 7.92 (m, 1H),7.38 (m, 1H), 7.28 (s, 1H), 7.14 (m, 1H), 4.90 (m, 1H), 4.70 (m, 1H),3.91 (m, 1H), 3.72 (s, 3H), 2.05-1.82 (m, 5H), 1.48 (m, 1H).

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Four different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT, 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GS1 peptide and 42 μMATP (containing 260,000 cpm ³³P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta.

In a third protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³3P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for onehour at room temperature in the presence of GSK3beta (total reactionvolume: 100 microliters).

In a fourth protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of ³³P-ATP) were incubated in 50 mM Hepes,pH 7.2, 1 mM DTT, 1 mM MgCl₂, 1 mM EGTA, 0.01% Tween 20 buffer for 90minutes at room temperature in the presence of commercial GSK3beta(Millipore) (total reaction volume: 100 microliters).

Inhibitors were solubilized in DMSO (final solvent concentration in thereaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated ³³P radioactivity was determinedby liquid scintillation spectrometry. The phosphorylated GS-1 peptidehad the following sequence: NH2-YRRAAVPPSPSLSRHSSPHQS(P)EDEE-COOH.(Woodgett, J. R. (1989) Analytical Biochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 are between 0.1 nanomolar to 3 micromolarconcentrations.

For example, on the protocol 4, the compound No. 1 of table 1 shows anIC₅₀ of 0.027 μM, the compound No. 8 of table 1 shows an IC₅₀ of 0.019μM, the compound No. 2 of table 2 shows an IC₅₀ of 0.030 μM.

Formulation Example (1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus.

Compound of Example 1 30 mg Crystalline cellulose 60 mg Corn starch 100mg  Lactose 200 mg  Magnesium stearate  4 mg

(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules.

Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20 mg

(3) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule.

Compound of Example 1 3 mg Sodium chloride 4 mg Distilled water forinjection 1 ml

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

What is claimed is:
 1. A compound of formula (I):

wherein: Y represents two hydrogen atoms, a sulphur atom, or an oxygenatom; R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidinering, the ring being optionally substituted by a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group or a halogen atom; R2 represents a hydrogen atom, aC₁₋₆ alkyl group or a halogen atom; R3 represents: a phenyl group, aphenyl-CH₂— group, a C₁₋₆ alkyl-O—C(O)— group, a phenyl-C(O)— group, a5-10 membered heterocyclic group, a phenyl-CH₂—O—C(O)— group, or a—C(O)-5-10-membered heterocyclic group, these groups being optionallysubstituted by 1 to 4 substituents selected from a C₁₋₆ alkyl group, ahalogen atom, a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenatedalkyl group, a hydroxyl group, a C₁₋₆ alkoxy group, a C₁₋₂perhalogenated alkoxy group, a C₁₋₆ alkylsulfonyl group, a nitro, acyano, an amino, a C₁₋₆ monoalkylamino group, a C₂₋₁₂ dialkylaminogroup, an acetoxy group, and an aminosulfonyl group; R4 represents ahydrogen atom, a halogen atom, a hydroxyl group, or a C₁₋₆ alkyl group;and m represents 1; or a salt thereof.
 2. The compound formula (I)according to claim 1:

wherein: Y represents two hydrogen atoms, a sulphur atom, or an oxygenatom; R1 represents a 4-pyridine ring or a 4 pyrimidine ring; R2represents a hydrogen atom; R3 represents: a phenyl group, a phenyl-CH₂—group, a C₁₋₆ alkyl-O—C(O)— group, a phenyl-C(O)— group, a pyridinegroup, a phenyl-CH₂—O—C(O)— group, a —C(O)-pyridine group, or a—C(O)benzodioxine group, these groups being optionally substituted by 1to 4 substituents selected from a halogen atom, and a C₁₋₆ alkoxy group;R4 represents a hydrogen atom, a hydroxyl group, or a C₁₋₆ alkyl group;and m represents 1; or a salt thereof.
 3. A compound selected from thegroup consisting of:(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-phenyl)-amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(5-chloro-2-methoxy-phenyl)-amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide;(+/−)-9-Methyl-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-2-methoxy-phenyl)-amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-benzyl)amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-methoxy-benzyl)amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(4-chloro-benzyl)amide;(+/−)-4-Chloro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid benzyl ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid ethyl ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid phenyl ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid (4-fluoro-phenyl) ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid (2-chloro-benzyl) ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid (2-methoxy-ethyl) ester;(+/−)-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-carbamicacid (2-methoxy-phenyl)ester;(+/−)-2,6-Dimethoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-nicotinamide;(+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide;(+/−)-2-Methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-nicotinamide;(+/−)-9-Hydroxy-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-pyridin-3-yl)-amide;(+/−)-4-Fluoro-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-ylmethyl)-benzamide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(pyridin-2-yl)amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2,6-dimethoxy-pyridin-3-yl)-amide;(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(pyridin-3-yl)amide; and(+/−)-4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylicacid N-(2-methoxy-pyridin-3-yl)-amide; or a salt thereof.
 4. A compoundof formula (II):

wherein R1 represents a 4-pyridine ring or a 4-pyrimidine ring; R2represents a hydrogen atom; m represents 1; and R represents an C₁₋₆alkyl group.
 5. A pharmaceutical composition comprising a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof and one or more pharmaceutical additives.
 6. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 2 ora pharmaceutically acceptable salt thereof and one or morepharmaceutical additives.
 7. A pharmaceutical composition comprising acompound of formula (I) according to claim 3 or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutical additives.
 8. Amethod of treating a neurodegenerative disease in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein the neurodegenerative disease isselected from the group consisting of Alzheimer's disease, Parkinson'sdisease, tauopathies, vascular dementia; acute stroke, traumaticinjuries; cerebrovascular accidents, brain cord trauma, spinal cordtrauma; peripheral neuropathies; retinopathies and glaucoma.
 9. A methodof treating a disease in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of formula (I)according to claim 1 or a pharmaceutically acceptable salt thereof,wherein said disease is selected from the group consisting ofnon-insulin dependent diabetes; obesity; manic depressive illness; andschizophrenia.
 10. A method of treating malaria in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 11. A method of treating Pemphigus vulgaris ina patient, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof.
 12. A method of treatingneutropenia induced by cancer chemotherapy in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 13. A process for the synthesis of compound offormula (I):

comprising reacting a compound of formula (II):

wherein R1 represents a 4-pyridine ring or a 4-pyrimidine, R2 representsa hydrogen atom, m represents 1, and R represents an C₁₋₆ alkyl group;with R3-NH₂ and R4-L, wherein R3 represents a phenyl group, aphenyl-CH₂— group, a C₁₋₆ alkyl-O—C(O)— group, a phenyl-C(O)— group, apyridine group, a phenyl-CH₂—O—C(O)— group, a —C(O)-pyridine group, or a—C(O)benzodioxine group, these groups being optionally substituted by 1to 4 substituents selected from a halogen atom and a C₁₋₆ alkoxy group;and R4 represents a hydrogen atom, a hydroxyl group, or a C₁₋₆ alkylgroup; and L represents a tosyl, a mesyl or a bromide.